Course: Organic Chemistry (University of Washington, Prof. Goldman) Source: Problem Set 4 Difficulty: Intermediate Prerequisites: SN2 reactions, nucleophilicity vs. basicity, stereochemistry (anti addition), Grignard reagents, leaving groups
Epoxides are three-membered cyclic ethers with significant ring strain, making them unusually reactive electrophiles. This problem set sits squarely in the nucleophilic substitution and ring-opening portion of an organic chemistry course, bridging what you learnt about SN2 reactions and stereochemistry with new electrophile types. If you can open an epoxide with a nucleophile and predict the regiochemistry and stereochemistry of the product, you have the core skill this unit tests.
Epoxides are strained rings that open readily under either acidic or basic/nucleophilic conditions. Acid-catalysed opening favours attack at the more substituted carbon (Markovnikov-like), while nucleophilic opening under basic conditions favours attack at the less substituted (less hindered) carbon. This problem set also tests multi-step sequences where epoxide ring-opening feeds into tosylation, elimination, and intramolecular cyclisation.
Epoxide (oxirane)
A three-membered cyclic ether. The roughly 60° bond angles create substantial ring strain, making epoxides far more reactive than ordinary ethers. In simple terms, think of it as a tightly wound spring that wants to snap open.
MCPBA (meta-chloroperoxybenzoic acid)
A peracid used to convert alkenes into epoxides via syn addition of an oxygen atom across the double bond. The reaction is stereospecific: a cis alkene gives a cis epoxide, and a trans alkene gives a trans epoxide.
Ring-opening reaction
Any reaction in which the epoxide's C–O bond breaks and a nucleophile forms a new bond to one of the ring carbons. The strain energy released is the thermodynamic driving force.
Anti addition (anti periplanar opening)
The nucleophile attacks from the face opposite the departing oxygen, producing a trans relationship between the nucleophile and the hydroxyl in the product. In simple terms, the incoming group and the oxygen end up on opposite sides.
Grignard reagent (RMgX)
An organomagnesium halide that acts as a strong nucleophile and base. Grignard reagents open epoxides at the less substituted carbon under basic conditions, extending the carbon chain.
Tosylate (OTs, TsCl / pyridine)
A tosylate is the sulfonate ester formed when an alcohol reacts with tosyl chloride (TsCl) in the presence of a base such as pyridine. Tosylation converts a poor leaving group (OH) into an excellent one (OTs) without changing the carbon skeleton or the stereochemistry at that carbon.
Intramolecular reaction
A reaction in which the nucleophile and the electrophilic centre are part of the same molecule. When a molecule contains both a nucleophile (e.g. an alkoxide) and a leaving group, cyclisation can occur. Forming five- and six-membered rings is kinetically favoured.
Regiochemistry of epoxide opening
Under acidic conditions, the nucleophile attacks the more substituted carbon (the one better able to stabilise partial positive charge). Under basic/nucleophilic conditions, the nucleophile attacks the less substituted (less sterically hindered) carbon, following standard SN2 selectivity.
Tags: MCPBA, peracid, epoxidation, syn addition, acid-catalysed ring opening, anti-dihydroxylation, trans-diol
Epoxidation step (Problem 1a, step 1)
MCPBA delivers an oxygen atom to the alkene via a concerted, syn mechanism.
The stereochemistry of the alkene is preserved in the epoxide: substituents that were cis remain cis.
For a cyclohexene with a substituent (as in 1a), MCPBA approaches the less hindered face preferentially, though both faces may react.
Acid-catalysed ring opening (Problem 1a, step 2)
H⁺/H₂O protonates the epoxide oxygen, making both ring carbons more electrophilic.
Water (the nucleophile) attacks the more substituted carbon. This is the key regiochemical point: acid conditions favour Markovnikov-like selectivity because the more substituted carbon bears more positive charge character in the protonated epoxide.
The attack is anti to the departing oxygen, giving a trans-1,2-diol (anti addition overall).
Net result of MCPBA then H⁺/H₂O: anti-dihydroxylation of the alkene. This is the stereochemical opposite of syn-dihydroxylation (OsO₄).
Real-world connection: Anti-dihydroxylation via epoxidation is used in pharmaceutical synthesis when the trans-diol stereochemistry is needed, such as in the Sharpless epoxidation/ring-opening sequence for chiral building blocks.
Tags: KCN, cyanide, nucleophilic opening, SN2, regiochemistry, anti addition, cyanohydrin
Nucleophilic opening with KCN (Problem 1b)
CN⁻ is a good nucleophile. Under basic/neutral conditions, it attacks the less substituted carbon of the epoxide (standard SN2 logic: less steric hindrance).
The attack is anti to the oxygen, and the oxygen picks up a proton during the H⁺ workup step to become an –OH group.
Product: a β-hydroxynitrile (the CN and OH are on adjacent carbons, trans to each other).
Identifying reagents from products (Problem 1c)
The starting material is cyclohexene, and the products are two brominated cyclohexanes (a pair with Br in axial and equatorial positions).
This transformation is an addition of HBr across the double bond, giving Markovnikov addition.
The reagent is HBr. The mixture of stereoisomers arises because the planar carbocation intermediate can be attacked from either face.
Reagents for an alcohol-to-epoxide conversion (Problem 1e)
The starting material is an allylic alcohol and the product is an epoxy alcohol (the double bond has been epoxidised while the OH remains).
The reagent is a peracid (MCPBA) or, for enantioselective work, the Sharpless epoxidation conditions (Ti(OiPr)₄, TBHP, diethyl tartrate).
The OH group can direct the epoxidation to occur on the same face as the hydroxyl through hydrogen-bonding interactions with the peracid.
Tags: Grignard, EtMgBr, tosylation, TsCl, pyridine, NaOMe, elimination, E2, SN2
Grignard opening of an epoxide (Problem 1d, step 1)
EtMgBr acts as a nucleophile (the ethyl carbanion equivalent). It opens the epoxide at the less substituted carbon, extending the carbon chain by two carbons.
Product after aqueous workup: a primary or secondary alcohol, depending on the epoxide's substitution pattern.
The Grignard is both nucleophilic and basic, so it follows the SN2 pathway at the less hindered carbon.
Tosylation (Problem 1d, step 2)
TsCl in pyridine (C₅H₅N acts as a base and solvent) converts the –OH from step 1 into an –OTs leaving group.
This step does not break any bonds to the carbon bearing the oxygen, so stereochemistry at that centre is retained.
Pyridine scavenges the HCl by-product.
Substitution or elimination with NaOMe (Problem 1d, step 3)
NaOMe (sodium methoxide) is both a nucleophile and a base.
With a primary tosylate, SN2 displacement gives a methyl ether.
With a secondary or tertiary tosylate, E2 elimination competes or dominates, yielding an alkene.
The outcome depends on the substrate's substitution: consider whether the tosylate carbon is primary, secondary, or tertiary to predict the major product.
Real-world connection: This three-step sequence (Grignard ring-opening, tosylation, displacement) is a classic chain-extension and functional group interconversion strategy used throughout synthetic organic chemistry.
Tags: intramolecular SN2, NaH, epoxide formation, Williamson ether synthesis, radical halogenation, isobutane, tert-butyl alcohol
Intramolecular cyclisation (Problem 1f)
The substrate is a chlorohydrin: a molecule with both a –Cl (leaving group) and an –OH (potential nucleophile) on the same chain.
NaH deprotonates the –OH to form an alkoxide (RO⁻), a strong nucleophile.
The alkoxide then attacks the carbon bearing the chloride in an intramolecular SN2 reaction.
The product is a cyclic ether (an epoxide if the ring is three-membered, or a larger ring depending on chain length).
Ring size matters: 3-membered (epoxide) and 5-membered (tetrahydrofuran) rings form readily. Count the atoms between the nucleophile and the leaving group to predict the ring size.
Synthesis from isobutane (Problem 4)
Target molecule: tert-butyl alcohol (2-methyl-2-propanol), based on the structure shown.
Isobutane has no functional group, so the first step must introduce one.
Step 1: Radical halogenation (Br₂, hv or heat) at the tertiary C–H bond. Bromine is selective for tertiary hydrogens. Product: tert-butyl bromide.
Step 2: SN1 substitution with water (or NaOH/H₂O). The tertiary substrate ionises readily to form a stable 3° carbocation, which is captured by water. Product: tert-butyl alcohol.
Alternatively: tert-butyl bromide + NaOH → tert-butyl alcohol (though at a tertiary centre, elimination competes, so mild aqueous conditions are preferred over strong base in a polar aprotic solvent).
Students often assume nucleophilic opening of an epoxide follows the same regiochemistry as acid-catalysed opening. It does not. Under basic conditions the nucleophile goes to the less substituted carbon (SN2 logic). Under acidic conditions it goes to the more substituted carbon.
Students frequently forget that epoxide ring-opening is always anti. The nucleophile and the departing oxygen end up trans to each other regardless of whether conditions are acidic or basic.
Tosylation is sometimes confused with a reaction that inverts stereochemistry. Tosylation retains configuration at the carbon bearing the –OH because the C–O bond is not broken. Inversion happens in the next step, when the tosylate is displaced by a nucleophile.
When planning a synthesis from an unfunctionalised alkane (like isobutane), students sometimes skip the halogenation step and jump straight to substitution. You cannot do substitution chemistry without first introducing a leaving group.
⚠️ Regiochemistry of epoxide opening is one of the most commonly tested points. Be ready to explain why acidic conditions give Markovnikov-like selectivity and basic conditions give anti-Markovnikov selectivity.
⚠️ Stereochemistry: expect to draw or identify the trans-diol product from epoxidation followed by acid-catalysed opening. Know that this is anti-dihydroxylation (contrast with syn-dihydroxylation using OsO₄).
⚠️ Multi-step synthesis problems that combine Grignard opening, tosylation, and displacement or elimination are a favourite exam format. Trace each intermediate carefully.
⚠️ Intramolecular reactions: if a molecule contains both a nucleophile and a leaving group at the right distance, cyclisation is often the expected answer. Count atoms to predict ring size.
⚠️ Synthesis from simple starting materials (alkanes): remember the sequence, functionalise first (radical halogenation), then transform.
True or false: MCPBA adds oxygen to an alkene with anti stereochemistry. (False, it is syn addition.)
Fill in the blank: Under acidic conditions, a nucleophile opens an epoxide at the ______ substituted carbon. (more)
True or false: Tosylation of an alcohol inverts the configuration at the carbon bearing the –OH. (False, configuration is retained because the C–O bond is not broken.)
Fill in the blank: NaH deprotonates an alcohol to form an ______. (alkoxide)
True or false: Grignard reagents open epoxides at the more substituted carbon. (False, they attack the less substituted carbon.)
Q: An alkene is treated with MCPBA followed by H⁺/H₂O. What is the overall transformation, and what is the stereochemical outcome?
A: The overall transformation is anti-dihydroxylation of the alkene. The product is a trans-1,2-diol. MCPBA forms the epoxide (syn), and the acid-catalysed ring opening occurs with anti selectivity.
Q: You have propylene oxide (1,2-epoxypropane). Predict the product of treatment with (a) KCN then H⁺ workup, and (b) H₃O⁺ then H₂O.
A: (a) CN⁻ attacks the less substituted carbon (C1) under basic conditions, giving 3-hydroxy-butanenitrile (the nitrile is on the primary carbon, the OH on C2). (b) H₂O attacks the more substituted carbon (C2) under acidic conditions, giving 1,2-propanediol with the –OH on C2 from the water.
Q: Why does tosylation followed by treatment with NaOMe sometimes give an elimination product rather than substitution?
A: NaOMe is both a nucleophile and a reasonably strong base. When the tosylate is on a secondary or tertiary carbon, E2 elimination competes with or dominates over SN2, because the steric hindrance at the electrophilic carbon disfavours backside attack while the base can still abstract a β-hydrogen.
Q: A chlorohydrin (Cl and OH on adjacent carbons) is treated with NaH. What forms and why?
A: An epoxide forms. NaH deprotonates the –OH to give an alkoxide, which displaces the Cl in an intramolecular SN2 reaction, forming the strained three-membered ring.
Q: Propose a two-step synthesis of tert-butyl alcohol from isobutane.
A: Step 1, radical bromination (Br₂, hv) at the tertiary C–H to give tert-butyl bromide. Step 2, hydrolysis under aqueous conditions (H₂O, or dilute NaOH) to give tert-butyl alcohol via SN1.
This material connects directly to SN2 and SN1 reactions from earlier in the course: epoxide ring-opening under basic conditions is an SN2 process, and understanding when elimination competes with substitution (the NaOMe step in Problem 1d) draws on the SN2/E2 competition framework.
The stereochemistry of anti addition here also ties to halogenation of alkenes (Br₂ addition through a bromonium ion), which follows the same anti addition pattern for the same mechanistic reason: backside attack on a three-membered ring intermediate.
Synthesis planning from unfunctionalised starting materials (Problem 4) reinforces the radical reaction chapter and the idea that organic synthesis is fundamentally about installing and transforming functional groups in a logical sequence.
epoxide, oxirane, MCPBA, peracid, meta-chloroperoxybenzoic acid, ring opening, acid-catalysed, nucleophilic opening, anti addition, trans-diol, anti-dihydroxylation, syn-dihydroxylation, OsO₄, Grignard reagent, EtMgBr, tosylate, TsCl, pyridine, leaving group, NaOMe, sodium methoxide, SN2, E2, intramolecular, Williamson ether synthesis, NaH, alkoxide, chlorohydrin, radical halogenation, isobutane, tert-butyl alcohol, tert-butyl bromide, carbocation, SN1, regiochemistry, stereochemistry, Markovnikov, anti-Markovnikov